Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Tom Sidwell; Yang Liao; Alexandra L Garnham; Ajithkumar Vasanthakumar; Renee Gloury; Jonas Blume; Peggy P Teh; David Chisanga; Christoph Thelemann; Fabian de Labastida Rivera; Christian R Engwerda; Lynn Corcoran; Kohei Kometani; Tomohiro Kurosaki; Gordon K Smyth; Wei Shi; Axel Kallies

doi:10.1038/s41467-019-14112-2

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Nat Commun. 2020 Jan 14;11(1):252. doi: 10.1038/s41467-019-14112-2.

Authors

Tom Sidwell^{1

2}, Yang Liao^{3

4}, Alexandra L Garnham^{3

4}, Ajithkumar Vasanthakumar^{1

2}, Renee Gloury^{1

2}, Jonas Blume^{1

2}, Peggy P Teh^{1

2

5

6}, David Chisanga^{3

4}, Christoph Thelemann², Fabian de Labastida Rivera⁷, Christian R Engwerda⁷, Lynn Corcoran^{2

4}, Kohei Kometani⁸, Tomohiro Kurosaki^{8

9}, Gordon K Smyth^{3

10}, Wei Shi^{3

11}, Axel Kallies^{12

13}

Affiliations

¹ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3010, Australia.
² Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.
³ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.
⁴ Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁵ Renal Medicine, Alfred Health, Melbourne, VIC, 3004, Australia.
⁶ Department of Nephrology, Western Health, St Albans, VIC, 3021, Australia.
⁷ QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
⁸ Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.
⁹ Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
¹⁰ School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, 3010, Australia.
¹¹ School of Computing and Information Systems, The University of Melbourne, Melbourne, VIC, 3010, Australia.
¹² Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3010, Australia. [email protected].
¹³ Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia. [email protected].

Abstract

Differentiation and homeostasis of Foxp3⁺ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic-Leucine Zipper Transcription Factors / deficiency
Basic-Leucine Zipper Transcription Factors / metabolism*
Cell Differentiation / immunology
Chromatin / metabolism
Colitis / immunology
Disease Models, Animal
Epigenesis, Genetic / immunology
Forkhead Transcription Factors / metabolism
Gastrointestinal Tract / immunology
Gene Expression Regulation / immunology
Homeostasis / immunology
Interferon Regulatory Factors / deficiency
Interferon Regulatory Factors / metabolism
Interleukin-10 / biosynthesis
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Receptors, Antigen, T-Cell / metabolism*
Signal Transduction / immunology
T-Lymphocyte Subsets / immunology*
T-Lymphocyte Subsets / metabolism
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism

Substances

Bach2 protein, mouse
Basic-Leucine Zipper Transcription Factors
Chromatin
Forkhead Transcription Factors
Foxp3 protein, mouse
IL10 protein, mouse
Interferon Regulatory Factors
Receptors, Antigen, T-Cell
interferon regulatory factor-4
Interleukin-10